Dr. Seddon is a professor of ophthalmology at Tufts Medical School and director of the Ophthalmic Epidemiology and Genetics Service at the New England Eye Center, Boston. She disclosed grant support from Genentech and that Tufts Medical Center has filed patent applications.
Dr. Sobrin is an associate professor of ophthalmology at Harvard Medical School and a member of the Retina and Uveitis Services of the Massachusetts Eye and Ear Infirmary, Boston. She had no disclosures.
Ms. Liu is a third-year medical student at Harvard Medical School.  She had no disclosures.
Age-related macular degeneration is considered a complex genetic disorder, which means that multiple genetic variants contribute incrementally to disease risk, and environmental factors also play a role in its pathogenesis. Age-related macular degeneration (AMD) is also one of the best genetically characterized of all diseases, with more than 30 loci identified, accounting for a substantial proportion of the heritability.1 Variants in the complement factor H (CFH) and LOC387715/ARMS2 (Age-Related Maculopathy Susceptibility 2) loci have the strongest effect on AMD development and progression,2 but variations in many other genes also contribute to the disease.3-5

The identification of these genetic loci has implicated several biological pathways in pathogenesis, such as the complement pathway, pathways for cholesterol and lipid metabolism, extracellular/collagen matrix, oxidative stress and angiogenesis signaling.5 In fact, AMD has become the paradigm for genetic discovery for complex disease with genetic loci discovered with family-based linkage studies, genome-wide association studies and next-generation sequencing approaches.6

Genetic Polymorphisms in AMD

The discovery of genetic polymorphisms in AMD not only provided important insights to the disease pathogenesis, but also promises to change clinical practice. Genetic polymorphisms have a potential impact on risk stratification and predicting therapy response.

Genetic information improves the clinician’s ability to predict progression to the advanced forms of AMD, choroidal neovascularization and geographic atrophy above and beyond the information garnered from macular findings and demographic and behavioral risk factors such as age, sex, smoking and education. A risk prediction model with 10 single nucleotide polymorphisms (SNPs) in eight different genes was highly predictive of progression with an area under the curve (AUC) of 91 percent.7 The genetic component of the model added approximately 10 percent to the AUC when compared to a model with macular phenotypes and demographic/environmental risk factors alone.  

Because of the genetic discoveries in AMD, genetic tests specifically for AMD are now widely available through physicians’ offices and in direct-to-consumer (DTC) packaging. Individuals can submit their DNA samples to a laboratory and receive information regarding their risk of AMD and many other diseases.  

Table 1. Studies of CFH Genotype Response to AREDS Supplementation in AMD

Studies of CFH and ARMS2 Genotype
No. of Subjects
Main Findings
Michael Klein, MD, et al. 200811 876 All genotype groups benefited although CFH high risk benefited less, may be driven by zinc component.
Johanna Seddon, MD, et al. 200912 1,446
Benefit of antioxidant-mineral supplement with the CFH homozygous low-risk genotype, but no benefit for homozygous risk genotype.
Johanna Seddon, MD, et al. 201113 2,937 Benefit of antioxidant-mineral supplement with the CFH homozygous low risk genotype, but no benefit for homozygous risk genotype.
Carl Awh, MD, et al. 201314 989 Differences in patients according to genotype:
• Some genotypes showed no benefit of any supplementation
• Some genotypes did better with zinc only or antioxidants only
Emily Chew, MD, et al. 201415 1,413 CFH and ARMS2 genotypes do not alter benefit of AREDS supplements
Carl Awh, MD, et al. 201516 989 Certain genotype groups had neutral or unfavorable responses (progression to advanced AMD) with supplements.
Emily Chew, MD, et al. 201517 526 In independent sample, results of Dr. Awh et al (2015) were not replicated
KEY: AREDS = Age-Related Eye Disease Study; ARMS2 = age-related maculopathy susceptibility 2; CFH = complement factor H.
In 2014, the American Academy of Ophthalmology (AAO) published recommendations for genetic testing of AMD, and specifically recommended to “avoid routine genetic testing for genetically complex disorders like AMD… until specific treatment or surveillance strategies have been shown in one or more published prospective clinical trials to be of benefit to individuals with specific disease-associated genotypes.”

The wide availability of genetic tests for AMD raises many questions. Many studies have investigated the differential benefits of specific AMD treatments based on genotypes, but do they meet the AAO standard on routine genetic testing? Are existing DTC genetic tests accurate and reliable to help patients obtain useful information about their individual risk of a complex genetic disease?

This article aims to summarize the current literature on AMD pharmacogenetics, provide an overview of DTC genetic testing, and touch upon important considerations when retina specialists encounter patients interested in commercial genetic testing for AMD.

The Evidence Regarding AREDS

The results of the Age-Related Eye Disease Study (AREDS) trial showed that supplements containing antioxidant vitamins plus zinc significantly reduced the odds of developing advanced AMD in patients with extensive intermediate size drusen, at least one large druse or noncentral geographic atrophy in one or both eyes.8 Eleven patients would need to be treated for seven years to prevent progression in one. From a public health perspective, investigators reported that if 8 million individuals at high risk for advanced AMD received treatment with the AREDS formulation, more than 300,000 would avoid disease progression and vision loss.9

In 2013, the AREDS2 trial found that beta carotene was associated with a higher incidence of lung cancers in former smokers and that an alternative regimen that substituted lutein and zeaxanthin for beta-carotene, was as effective in reducing the risk of developing advanced AMD.10 Recently, several studies have looked at the influence of genotypes on treatment response to AREDS vitamin supplementation. CFH (Y420H, rs1061170) and LOC387715/ARMS2 (A69S, rs10490924) were the two genetic loci the studies focused on because they both have strong effect sizes and are related to progression from early and intermediate AMD to advanced stages in the AREDS cohort.2 The studies found conflicting results, particularly around the interaction between CFH genotypes and zinc supplementation. The studies have investigated different patient subsets enrolled in the original AREDS trial.

In the first study of pharmacogenetics related to the AREDS formulation, Michael Klein, MD, and colleagues in 2008 evaluated 876 individuals with intermediate or unilateral advanced AMD at baseline (Table 1).11 They assigned patients to four treatment groups: placebo (n=204), antioxidants alone (n=219), zinc alone (n=217), or antioxidants and zinc (n=236).

The investigators found evidence of a possible interaction between CFH genotype and treatment with zinc—specifically, that participants who were homozygous for the non-risk allele (TT) at CFH loci had greater reduction in AMD progression than individuals with risk alleles (CC), 68 percent  versus 11 percent, when treated with antioxidants and zinc instead of placebo (p=0.03).11 They also found positive interaction between zinc supplementation and CFH genotype (p=0.004).

However, Dr. Klein and colleagues also found that all groups, including patients with high-risk CFH alleles, benefited from AREDS supplementation. They concluded that genetic testing was not indicated because supplementation benefited every group to some degree.

Controversies in AREDS

Johanna Seddon, MD, MSc, and colleagues in 2009 and 2011 expanded their previous analyses in 2007 and 2008,2,11 and published risk progression models for progression to AMD, and both analyses showed positive interactions between CFH genotype and treatment groups (Table 1).12,13 In particular, these models showed that combined antioxidant-zinc supplementation derived a greater benefit than placebo for subjects with the homozygous non-risk genotype, but the benefit did not extend to the those with the homozygous risk genotype. The study did not find any interactions between antioxidant/mineral supplements and other genetic variants.

Carl Awh, MD, and colleagues reported findings in 2013 that were consistent in some respects with the previous reports, but also brought into question the effectiveness of AREDS formulation in patients with different genotypes (Table 1).14 This study included patients with AREDS category 3 disease in at least one eye. These authors found  a positive interaction between placebo vs. zinc treatment groups and CFH risk alleles. They also reported that patients homozygous for CFH risk alleles and without ARMS risk alleles treated with zinc had a 43 percent greater progression rate by 12 years compared with those treated with placebo.

Dr. Awh’s group estimated that these patients could have a 56 percent reduction of 10-year progression to advanced disease with antioxidants alone rather than the AREDS formulation. Individuals with one CFH risk allele and no ARMS2 risk alleles could have a 29 percent reduction in progression rate with antioxidants rather than the AREDS formulation.

Based on these findings, the authors recommended treating patients with different nutritional supplements based on their genotypes. Limitations for which this study was criticized were selective subgroup post-hoc analysis and testing multiple hypotheses without sufficient correction for multiple testing.

After these studies Emily Chew, MD, of the National Eye Institute led a study examining 1,413 AREDS participants for whom genotyping was available.15 This investigation  concluded that no interactions existed between genotypes and AREDS supplementation (p=0.06, Table 1). One critique of this study was that it was significantly underpowered to evaluate certain subgroups for clinically important interactions; certain subgroup analyses had fewer than 10 patients.

More recently, Dr. Awh’s team published another analysis with the same 989 participants from their original article.16 Again, they found positive interactions between zinc and AREDS treatment with the genotypes (Table 1). They also found that patients with two CFH risk alleles and no ARMS2 risk alleles progressed more with zinc-containing treatment than with placebo, with a hazard ratio of 3.07 (p=0.0196) for zinc and 2.73 (p=0.0418) for AREDS formulation.

For patients with zero or one CFH risk alleles and no ARMS2 risk alleles, neither zinc nor AREDS altered progression of disease compared to placebo, while antioxidants decreased progression.

For patients with two CFH risk alleles and one or two ARMS2 risk alleles, no treatment was better than placebo. The authors concluded that the benefit of the AREDS formulation was a result of favorable response by patients in only one genotype group, balanced by neutral or unfavorable responses in three other genotype groups. 
Simultaneously, Dr. Chew and her group published an analysis that used Dr. Awh’s methods but applied them to a different cohort of 526 AREDS patients.17 The results varied significantly from those Dr. Awh’s group reported.

Specifically, in the group with zero or one CFH risk alleles and no ARMS2 risk alleles, the residual cohort showed a marked beneficial treatment effect of the AREDS supplement and a smaller beneficial effect of zinc. In contrast, for this same genotype, Dr. Awh’s group found that only antioxidant supplementation was beneficial.

Participants in the residual cohort with two CFH risk alleles and no ARMS2 risk alleles also benefited from AREDS supplements—again, in contrast with the 2.73-fold increase in progression seen in the cohort in Dr. Awh’s report.

Dr. Chew and her associates found that all four genotype groups in the residual cohort benefited from the AREDS combination of antioxidant and zinc. They could not replicate the results from Dr. Awh’s group using the residual cohort, and suggested that Dr. Awh’s findings were likely false positives due to the multiplicity of genetic subgroups examined, the large number of potential comparisons without sufficient correction of the p values and the lack of a pre-specified hypothesis.17

Why Comparisons Are Difficult

The different analytic approaches of the initial studies examining response to AREDS supplementation by genotype make it difficult to compare them directly. We can say that the earlier analyses indicated that some interaction may exist between zinc supplementation and CFH genotype. However, identical analytic methods could not replicate this in a different independent, although relatively small sample.17

The initial findings were also based on post-hoc subgroup analyses and, thus, do not meet the AAO criteria for data from a prospective study to prove the clinical utility of genetic testing. So the evidence currently is not sufficient to warrant genetic testing for decision-making regarding AREDS supplementation. However, initial studies on this topic11–13 are suggestive of an interaction, so this cannot be ruled out.

Worth noting is that genetic testing is currently recommended for ocular diseases, such as retinal degenerations that are considered to be Mendelian genetic disorders.  In Mendelian conditions, a mutation in one gene is generally sufficient to cause disease, and environmental factors to date have not been shown to play a major role in disease development.

For Mendelian diseases, the AAO recommendations have not required prospective data to prove clinical utility; the thinking is that clinical utility is derived from the diagnostic and genetic counseling information that genetic testing provides. For AMD, most agree and the literature demonstrates that the genetic information is useful for prediction, and many patients are interested in knowing their genetic risk, but we do not yet know for sure if this will lead to better outcomes.

Pharmacogenetics of Anti-VEGF Agents

Small studies have shown a potential differential response of intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents for wet AMD according to genotype, but larger, well-powered trials have not.

Most data from smaller studies supported that having risk alleles at the CFH Y402H and ARMS2 loci were associated with worse visual outcome after anti-VEGF therapy, thus requiring additional intravitreal injections.18–24 Also, some conflicting results have reported that higher-risk genotypes at CFH and VEGF genetic loci were associated with better visual outcomes.25

However, the results of the better-powered and prospective Comparison of Age-related Macular Degeneration Treatment Trials (CATT) and Inhibition of VEGF in Age-related Choroidal Neovascularization (IVAN) study found no significant associations between any genetic variants and response to anti-VEGF therapy.26,27 Prospective trials do not indicate that genetic testing is clinically informative when making decisions on anti-VEGF treatment.

Similarly, the data for pharmacogenetics of response to photodynamic therapy are also conflicting. Three studies showed no effect of CFH genotype on response to photodynamic therapy.28–30 One study showed better visual outcomes with high-risk alleles at the CFH loci,31 and another showed worse visual outcome with high-risk alleles.32

Studies have also investigated other genetic loci, such as the prothrombin gene, methylenetetrahydrofolate reductase, factor XIII-A, VEGF, and HTRA1, but these studies have involved modest numbers of patients and none of the reported associations has been consistently and independently replicated.33–36 Photodynamic therapy is rarely used for AMD today, so data may not ever exist to determine the usefulness of genetic testing for predicting response to this therapy.

Direct-to-Consumer Genetic Testing

While more evidence would be helpful to support physician-ordered genetic testing for AMD patients, some patients may pursue genetic testing on their own. Retina specialists need to be aware of the available tests so that we can counsel patients who present them with the results.

The rise of the personal genomics industry can be traced back to 2007 with the launch of DTC services from deCODE genetics and 23andMe, a Google-backed startup.37 Since then, many genetic testing companies have launched DTC genetic tests, and AMD is one of the most commonly tested eye diseases among them.37

Table 2. Commercially Available Direct-to-Consumer Genetic Tests

Test company
DNA Source
No. of SNPs
Australia; USA
Buccal swab
CFH rs1061170
C2 rs800292
Test Country
Unknown $299*
DNA Genie
Bucca swab
Blood (Guthrie card)
CFH rs1061170
C2 rs800292
International Biosciences
UK; Slovenia
Blood (Guthrie card)
Unknown $377*†
Accu-metricsCanadaBuccal swab
Unknown $299**
* Part of 25-disease panel
** Part of 30-disease panel
† U.S. dollar equivalent
Key: SNP = single nucleotide polymorphisms; C2 = complement  component 2; CFH = complement factor H.

We compared and contrasted six DTC AMD genetic tests currently available to consumers in the United States for the following characteristics: DNA source, number of SNPs, specific single-nucleotide polymorphisms (SNPs) tested and cost (Table 2). The companies accept DNA samples in the form of blood, buckle swab or saliva. The number of SNPs varies between two and 15.

A 2014 study by Gabriella Buitendijk and colleagues in the Netherlands evaluated the concordance of results from DTC AMD genetic tests by 23andMe, deCODEme, Easy DNA and Genetic Testing Laboratories. They performed the genotype analysis in their own laboratory.38 They found considerable variation of estimated risks among the four commercial tests in the three tested individuals, from a 1.6-fold difference for overall relative risk to an up to 12-fold difference for lifetime risk.

In one individual, one of the four tests indicated a higher-than-average genetic risk for AMD while another showed a lower-than-average genetic risk. The difference of estimated risks between the commercial tests and the validated prediction model was also significant—1.4 percent to 16.1 percent in DTC tests versus 0.5 percent to 4.2 percent in a validated prediction model. The authors attributed this discrepancy to the testing of only a limited set of genetic markers, the suboptimal choice of reference population that does not accurately reflect the consumer’s ancestry and life expectancy, and the methodology applied for risk calculation.

A study that evaluated risks of a wide range of diseases showed that AUC values of DTC tests differed significantly among the diseases and among the different tests for common complex diseases.39 The authors even showed that the formulas one company used could lead to a predicted risk exceeding 100 percent in high-risk cases. Retina specialists should warn patients about these perils and possible inaccuracies of DTC genetic tests. Other genetic tests not evaluated in that study may be more accurate.


Genetic testing holds great promise in the care of AMD patients. The extensive genetic discovery and excellent risk-prediction models developed thus far are the first step. Prospective studies would be helpful to show that predicting increased disease risk will make a difference in AMD patient outcomes and to determine whether patients with various genotypes would benefit from interventions such as more frequent in-office examinations, more rigorous home monitoring of disease or counseling about the importance of behavioral modification.

If these interventions produce better patient outcomes, then more evidence would exist to justify clinical genetic testing, according to the AAO. A randomized trial, however, would be expensive and difficult to execute, due to the availability of lifestyle counseling and monitoring already in place for high-risk patients.

Moreover, considerable evidence suggests that higher-risk genotypes increase rates of progression and subsequent visual loss among individuals with the same baseline phenotypes, and methods are now available to obtain this information for those who desire it. Also, treatment-genotype interaction is likely to be confirmed for some AMD treatments in the near future, which would alter the course of such studies.

AMD has a strong genetic component. Should family members have the opportunity to learn about their genetic risk? Should individuals at particularly high risk, with presence of both common and rare alleles, for example, be identified for family counseling about healthy lifestyles, or get ocular examinations, or receive any other type of counseling and care? Should industry be stratifying patients in clinical trials according to a composite score that includes genetic risk groups, to determine who will benefit most?7,12,13 Additional exciting research is underway that will hopefully answer these questions.  RS

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